The production of chromosomal alterations in human lymphocytes by drugs known to interfere with the activity of DNA topoisomerase II. I. m-AMSA.

The frequencies of chromosomal aberrations and sister chromatid exchanges (SCE) were studied in human peripheral lymphocytes after exposure of whole blood cultures to the antitumour agent m-AMSA. Chromosome-type aberrations were found in cells exposed before stimulation or during the G1-phase of the cell cycle. Chromatid-type aberrations were obtained in cells exposed during the S- and G2-phases, but also in cells exposed the G1-phase or before stimulation. Treatment of lymphocytes with m-AMSA in the G1-phase or before stimulation had the additional effect of strongly increasing the frequency of SCE. When unstimulated lymphocytes were exposed to m-AMSA, the frequencies of SCE and chromatid-type aberrations, but not the frequency of chromosome-type aberrations, could be strongly reduced by holding the cells in F-10 for 2-4 h before stimulation, or by changing the growth medium after stimulation. A 1-h incubation in growth medium was sufficient for obtaining this reduction. The medium in which the m-AMSA-treated cells were incubated for the first 3 h after stimulation proved to be capable of inducing chromatid-type aberrations in late S/G2-phase and SCEs in the S-phase. These observations show that the chromatid-type aberrations and SCEs obtained by exposing unstimulated lymphocytes to m-AMSA were not produced during the treatment itself, but after stimulation at an advanced stage of the cell cycle by an active substance (m-AMSA or a metabolite of m-AMSA) released into the medium during the first hours of incubation. Post-treatments in G2 with 1-beta-D-arabinofuranosylcytosine (ara-C) and hydroxyurea strongly enhanced the frequency of chromatid-type aberrations obtained after treatment of stimulated or unstimulated lymphocytes with m-AMSA. Post-treatments in unstimulated or G1-phase lymphocytes with ara-C did not influence the frequency of chromosome-type aberrations induced by m-AMSA at these stages, but strongly enhanced those induced by X-rays.